Dose-optimization of dasatinib is an important strategy in chronic myeloid leukaemia (CML) to balance efficacy, safety, and cost. While Western studies have explored low-dose approaches, data from India remain limited. We conducted a comparative study of 143 newly diagnosed chronic-phase CML patients, allocated to dasatinib de-escalation (DD, n = 80) after an initial 100 mg standard dose or upfront low-dose (50 mg) dasatinib (LD, n = 63). At 3 months, a significantly higher proportion of patients in the DD cohort achieved BCR-ABL1 ≤ 10% compared to LD cohort (98.4% vs. 72.1%, p < 0.001). At 6 months, ≤ 1% BCR-ABL1 was observed in 98.3% vs 83% (p = 0.014), while at 12 months, MMR rates were comparable, 93.2% vs. 79.5% (p = 0.120). Median FFS was not reached in DD cohort and was 49 months in LD cohort, with an estimated 5-year FFS rates of 80% and 50%, respectively (p = 0.117). Treatment discontinuation was more frequent in LD cohort (29.5%) compared to DD cohort (6.9%). No patient progressed to advanced phase CML or died during follow-up. Dasatinib de-escalation after 100 mg standard dose achieved superior early response, fewer discontinuations, and sustained outcomes versus upfront low-dose therapy. This first Indian study supports de-escalation as an effective, real-world dose-optimization strategy.